Activation of nuclear factor kappa B through the IKK complex by the topoisomerase poisons SN38 and doxorubicin: A brake to apoptosis in HeLa human carcinoma cells

The transcription factor nuclear factor (NF) KB is involved in the regulati on of cell survival. NF kappaB is activated in many malignant tumors and se ems to play a role in the resistance to cytostatic treatments and escape fr om apoptosis. We have studied the effects on NF kappaB activation of two to poisomerase poisons and DNA damaging agents that are used in chemotherapy: SN38 (7-ethyl-10-hydroxycamptothecin), the active metabolite of CPT11, and doxorubicin. In HeLa cells, both drugs activate NF kappaB using a preexisti ng pathway that requires a functional I kappaB-specific kinase complex, I k appaB-specific kinase activation, I kappaB-alpha phosphorylation, and degra dation. Blocking NF kappaB activation by stable expression of a mutant supe r-repressor I kappaB-alpha molecule sensitized HeLa cells to the apoptotic actions of drugs and tumor necrosis factor. RNase protection assay analysis demonstrate that NF kappaB is involved in the regulation of a complex patt ern of gene activation and repression during the cellular response of HeLa cells to topoisomerase poisons. The blockade of NF-kappaB activation seems to shift the death/survival balance toward apoptosis.